Cell death domains (DD) are about 80 amino acid long modular units present in many proteins involved in apoptosis. Recent evidence has demonstrated that these domains are involved in protein-protein interactions; however, very little is known about the full range of their natural ligands. This application proposes in Phase I to examine the molecular recognition of the DD using combinatorial peptide libraries. Bacteriophage M13-displayed random peptide libraries will be screened by affinity selection with bacterially expressed fusion proteins of the TNF-, NGF-, and Fas-receptor DD's. The identity of binding peptides will be deduced by DNA sequencing and confirmed with synthetic peptides. In Phase II of the grant, the peptide ligands and new DD's will be used to establish high-throughput screens of combinatorial chemical libraries for the purpose of identifying drug leads that act by interfering with the interaction of proteins involved in apoptotic pathways. Antagonists of the interaction of apoptotic proteins may prove valuable in the treatment of numerous diseases. PROPOSED COMMERCIAL APPLICATION Peptidic Surrogate Ligands will be used to identify chemical compounds (leads) for drugs that modulate cell death pathways for the purpose of disease treatment.